Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients.
OBJECTIVE
Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes.


METHODS
We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 +/- 4 kg/m2, age 55 +/- 6 years) or placebo (BMI 27 +/- 4 kg/m2, age 58 +/- 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 +/- 4 kg/m2, age 55 +/- 7 years). Euglycemic-hyperinsulinemic clamp tests combined with D-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP). 1H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids.


RESULTS
High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by approximately 33 and approximately 48% (P < 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatin-treated patients, changes in LDL cholesterol related negatively to changes in M (r = -0.796, P < 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r = -0.840, P < 0.01) and positively to plasma retinol-binding protein-4 (r = 0.782, P = 0.008).


CONCLUSIONS
High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.
Szendroedi
Julia
J
Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria.
Anderwald
Christian
C
Krssak
Martin
M
Bayerle-Eder
Michaela
M
Esterbauer
Harald
H
Pfeiler
Georg
G
Brehm
Attila
A
Nowotny
Peter
P
Hofer
Astrid
A
Waldhäusl
Werner
W
Roden
Michael
M
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D010919:Placebos; D012016:Reference Values; D019821:Simvastatin / Q000627:therapeutic use*
D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005230:Fatty Acids, Nonesterified; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D008055:Lipids; D010919:Placebos; D019821:Simvastatin; D005947:Glucose